A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential

Autor: Delphine Rigault, Francine Acher, Nadia Oueslati, Hervé Daniel, Marianne Amalric, Isabelle Brabet, Jean-Philippe Pin, Heather McLean, Hugues-Olivier Bertrand, Tiphanie Courtiol, Bruno Vilar, Thomas Bessiron, Cyril Goudet, Thierry Deltheil
Přispěvatelé: Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Accelrys SARL, Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS) - Université Montpellier 2 - Sciences et Techniques (UM2) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Montpellier 1 (UM1) - Université de Montpellier (UM), Université Paris Descartes - Paris 5 (UPD5) - Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU) - Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11) - Centre National de la Recherche Scientifique (CNRS)
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Male
Patch-Clamp Techniques
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
MESH: Antiparkinson Agents
[SDV.NEU.PC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior
MESH : Dose-Response Relationship
Drug
Pharmacology
Ligands
Receptors
Metabotropic Glutamate
Synaptic Transmission
Biochemistry
MESH: Mice
Knockout
MESH: Dose-Response Relationship
Drug
Antiparkinson Agents
MESH: Recombinant Proteins
Mice
0302 clinical medicine
MESH: Structure-Activity Relationship
MESH : Structure-Activity Relationship
Excitatory Amino Acid Agonists
MESH: Ligands
MESH: Animals
MESH : Patch-Clamp Techniques
Receptor
Mice
Knockout
MESH : Synaptic Transmission
MESH : Ligands
0303 health sciences
Molecular Structure
[SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior
MESH : Rats
Chemistry
Metabotropic glutamate receptor 4
MESH : Receptors
Metabotropic Glutamate
Glutamate receptor
[SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences
Glutamate binding
MESH : Antiparkinson Agents
MESH : Phosphinic Acids
Recombinant Proteins
MESH : Mutagenesis
Site-Directed
MESH: Mutagenesis
Site-Directed
MESH: HEK293 Cells
Metabotropic glutamate receptor 1
MESH: Phosphinic Acids
Biotechnology
Agonist
MESH: Rats
MESH : Recombinant Proteins
medicine.drug_class
MESH : Male
MESH: Molecular Structure
MESH : Rats
Wistar
Structure-Activity Relationship
03 medical and health sciences
MESH : Mice
MESH: Patch-Clamp Techniques
Genetics
medicine
MESH: Synaptic Transmission
Animals
Humans
Rats
Wistar
MESH: Receptors
Metabotropic Glutamate
Molecular Biology
MESH: Mice
030304 developmental biology
MESH : Excitatory Amino Acid Agonists
Binding Sites
MESH: Humans
Dose-Response Relationship
Drug
MESH : Humans
[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
MESH: Rats
Wistar
Phosphinic Acids
MESH: Male
Rats
MESH : HEK293 Cells
HEK293 Cells
Metabotropic receptor
MESH: Binding Sites
Metabotropic glutamate receptor
Mutagenesis
Site-Directed
MESH : Mice
Knockout
MESH : Animals
MESH: Excitatory Amino Acid Agonists
MESH : Molecular Structure
MESH : Binding Sites
[SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences
030217 neurology & neurosurgery
Zdroj: FASEB Journal
FASEB Journal, Federation of American Society of Experimental Biology, 2012, 26 (4), pp.1682-93. ⟨10.1096/fj.11-195941⟩
FASEB Journal, 2012, 26 (4), pp.1682-93. ⟨10.1096/fj.11-195941⟩
FASEB Journal, Federation of American Society of Experimental Biology, 2012, 26 (4), pp.1682-93. 〈10.1096/fj.11-195941〉
ISSN: 0892-6638
1530-6860
DOI: 10.1096/fj.11-195941⟩
Popis: International audience; Metabotropic glutamate (mGlu) receptors are promising targets to treat numerous brain disorders. So far, allosteric modulators are the only subtype selective ligands, but pure agonists still have strong therapeutic potential. Here, we aimed at investigating the possibility of developing subtype-selective agonists by extending the glutamate-like structure to hit a nonconsensus binding area. We report the properties of the first mGlu4-selective orthosteric agonist, derived from a virtual screening hit, LSP4-2022 using cell-based assays with recombinant mGlu receptors [EC(50): 0.11 ± 0.02, 11.6 ± 1.9, 29.2 ± 4.2 μM (n>19) in calcium assays on mGlu4, mGlu7, and mGlu8 receptors, respectively, with no activity at the group I and -II mGlu receptors at 100 μM]. LSP4-2022 inhibits neurotransmission in cerebellar slices from wild-type but not mGlu4 receptor-knockout mice. In vivo, it possesses antiparkinsonian properties after central or systemic administration in a haloperidol-induced catalepsy test, revealing its ability to cross the blood-brain barrier. Site-directed mutagenesis and molecular modeling was used to identify the LSP4-2022 binding site, revealing interaction with both the glutamate binding site and a variable pocket responsible for selectivity. These data reveal new approaches for developing selective, hydrophilic, and brain-penetrant mGlu receptor agonists, offering new possibilities to design original bioactive compounds with therapeutic potential.
Databáze: OpenAIRE
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